The World Health Organization, a U.S. National Institutes of Health Consensus Development Conference and the U.S. Surgeon General have concluded that the oral use of snuff is carcinogenic to humans. In view of about 10 million current and further escalating numbers of snuff users in the U.S.A., and in view of the fact that more and more children and adolescents take up the habit of snuff-dipping, an epidemic of oral cancer may be anticipated. The presence of carcinogenic agents in snuff has been extensively documented, in that volatile and especially carcinogenic tobacco- specific N-nitrosamines, polynuclear aromatic hydrocarbons, and polonium-210 have been identified in snuff products. Bioassays of snuff carried out thus far, have led to benign and malignant tumors of the oral cavity in laboratory animals, however, the tumor yields were statistically insignificant. On the basis of a successful preliminary model assay in rats utilizing daily insertion of test materials into a surgically created test canal in the lower lip, and based on the observation that the snuff components, nicotine and N-nitrosamines, are quickly absorbed, we propose to establish significant documentation of the carcinogenicity of snuff in the oral cavity of laboratory animals. We also plan to investigate the induction and reversibility of chemical lesions in the tissues of the snuff-treated lip mucosa by studying the fate of DNA-adducts formed with reactive chemical species deriving from the snuff constituents. Furthermore, we intend to examine whether there are certain agents in the snuff which may inhibit the induction of tumors.